tbuckley/cabot-search huggingface dataset:
Abstract 14227: Development of a Tool To Improve Risk Stratification of Patients With Atrial Fibrillation in the Emergency Department
Authors: Travis L Anderson, Tiffany Armbruster, Ari Becker, Lindsey Rosman, Darren DeWalt, Laura Loehr, Anil Gehi
Journal: Circulation (2022)

Introduction: Currently, no tool exists to help emergency department (ED) physicians determine which patients with atrial fibrillation (AF) may be low risk for adverse outcomes and potential candidates for expedited discharge. Hypothesis: A simple decision aid can assess 90-day risk for a combined outcome of mortality, stroke, or re-presentation to the ED in AF patients. Methods: Through multi-disciplinary meetings, clinically relevant and easily attainable factors were selected to risk stratify AF patients in the ED, including: primary ED diagnosis (AF or other), age, AF symptom severity (Canadian Cardiovascular Society - Symptom of AF [CCS-SAF]), heart rate, blood pressure, and laboratory assessment. Logistic regression analyses were used to develop a scoring tool. Results: Over 15 months (Jan 2015 - Mar 2016), 935 consecutive patients presenting to the ED of an academic medical center hospital (University of North Carolina) with AF were included in the cohort. Ninety days from presentation, there were 275 (29.4%) adverse events. In multivariable analyses, 4 factors were identified which independently associated events among all patients with AF: non-AF primary ED diagnosis, age, heart rate, and severe AF symptoms (CCS-SAF 4). Using a scoring tool with these 4 factors (range 0-18), a score ≥ 14 predicted events with 72% accuracy. Including only the 223 patients with a primary diagnosis of AF, using a scoring tool with 3 factors (age ≥ 70, heart rate ≥ 105, severe AF symptoms) a score ≥ 10 (range 0-13) predicted events with 78% accuracy (25% sensitivity, 95% specificity). Conclusions: A simple risk stratification scoring tool may be useful to determine patient disposition for AF patients in the ED. In patients with a primary diagnosis of AF, the scoring tool was particularly useful (95% specific) in identifying patients unlikely to have an event. Further analyses of larger data sets are required for validation.
Abstract 12842: Adipose Tissue Derived Ceramides Regulate the Myocardial Redox State and Predict Cardiovascular Outcomes
Authors: Murray D Polkinghorne, Nadia Akawi, Ileana Badi, Antonio Checa, Christos Kotanidis, Ioannis Akoumianakis, Alexios S Antonopoulos, George Krasopoulos, Rana Sayeed, Nicholas Walcot, Keith M Channon, Craig Wheelock, Charalambos Antoniades
Journal: Circulation (2022)

Introduction: Ceramides biosynthesis is dysregulated in obesity, yet their role as mediators of obesity-induced myocardial dysfunction is unclear. Objective: We investigate the causal role of AT-derived ceramides in regulating the myocardial redox state and explore their prognostic value in patients with CVD. Methods: In 880 cardiac surgery patients, 20 sphingolipids were measured in plasma, subcutaneous-, thoracic- and epicardial-AT biopsies and their secretomes. Myocardial redox state was measured and the contribution of NOXs, uncoupled eNOS and mitochondrial oxidases to O 2 .- production quantified. Median follow-up was 8.3 years. Genetic variants were identified to predict CVD outcomes using cis-Mendelian Randomisation. The underlying mechanisms were explored using differentiated H9c2 cardiomyocytes in vitro and human myocardial tissue ex vivo . Results: C16:0-ceramide (CerC16) was the most abundant ceramide secreted from AT (p&lt;0.0001). Patients with high plasma CerC16 and C16:0-glucosylceramide (GlcC16) had significantly increased myocardial O 2 .- production (vs low/int.) (A) . Patients with rs112572487 (B) , an intronic SNP in UGCG , had significantly increased plasma GlcC16 (C) and myocardial NOX-derived O 2 .- (D) vs those without. Exogenous CerC16 (20nM) induced O 2 .- production in H9c2 cardiomyocytes and human myocardial tissue (E) , an effect prevented by the UGCG inhibitor D-PDMP. Importantly, high plasma GlcC16 led to a higher risk of cardiac death and/or heart failure (HR=2.128 [1.101, 4.115], p=0.025) vs low/int. levels, a relationship also seen with rs112572487 (F) . rs112572487 also led to an increased risk of new, post-operative atrial fibrillation in hospital (HR=1.805 [1.188, 2.742], p=0.006). Conclusions: We demonstrate for the first time, that AT-derived ceramides are causally related with dysregulated myocardial redox signalling and adverse cardiovascular disease outcomes in patients with advanced atherosclerosis.
Abstract 14201: Decoding the Genetic Regulation of Cardiac Long Noncoding RNAs in Male and Female Mice Using Integrative Genomic Analysis
Authors: Marlin Touma, Yang Cao, Calvin Pan, Aldons J Lusis
Journal: Circulation (2022)

Introduction: Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators of mammalian heart development and potential contributors to human cardiovascular diseases by regulating RNA transcription and processing. However, the genetic regulation lncRNAs and their interactions with mRNAs are poorly understood. Hypothesis: Cardiac lncRNAs are genetically regulated and they differentially modulate mRNA expression in female vs male hearts. Methods: Deep RNA-seq was performed using Illumina HiSeqTM 4000 sequencer protocol. SNP Array was used for mouse genotyping. Weighted Gene Co-expression Network Analysis (WGCNA) was conducted using R. Association analyses were performed using FaST-LMM. Results: To elucidate lncRNA-mediated transcriptional regulation in heart, we performed integrated genomic analysis of RNA-seq derived transcriptome and SNP genotype data from the hybrid mouse diversity panel (HMDP) of adult male and female mice hearts across 100 strains. Using a 5% FDR P value threshold, genome-wide quantitative trait locus (eQTL) analysis detected total of 408513 and 404661 locally associated (within 1 Mb of genomic distance of a given gene) SNP-lncRNA pairs in female vs male heart, respectively, which corresponded to 6977 and 6357 unique lncRNAs in female vs male heart, respectively. After excluding those with distal eQTLs ( P &lt;4.1e-6), 2687 and 2684 cardiac lncRNAs with cis eQTLs were retained. WGNCA revealed distinct lncRNA-mRNA modules. From module-trait correlation analysis, 14 female and 5 male modules correlated with heart weight, body fat, or insulin resistance (Bicor &gt;0.3, P &lt;0.05). By applying eQTL analysis to the module eigengenes, 11 modules were identified with eigengenes QTLs (FDR&lt;0.05). Lastly, a novel SNP-lncRNA-mRNA regulatory circuit involving the mitochondria transcription elongation factor, TSFM, was revealed from our analysis. Conclusions: We present our efforts to investigate lncRNA-mediated regulation of gene expression in female vs male mouse heart across 100 different strains. Our results reveal novel associations on lncRNAs with complex clinical traits and provide resources to facilitate mechanistic exploration of lncRNAs contribution to cardiovascular diseases.
Abstract 14022: Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity
Authors: Brian Yu, Afaf E Osman, Nikola Sladojevic, Nicole Prabhu, Haw-Chih Tai, Daiqing Chen, Gerardo Perla, Linus Park, Richard A Larson, James K Liao
Journal: Circulation (2022)

Introduction: Second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAE) in patients with Philadelphia-chromosome positive (Ph+) leukemia. Hypothesis: We hypothesized that second and third generation BCR-ABL1 TKIs may cause CVAE through activation of Rho-associated protein kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3, 5-37]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro , which could contribute to CVAE. Results: Patients receiving second and third generation TKIs had 1.6-fold greater ROCK activity compared to both patients receiving imatinib and control patients. Elevated ROCK activity was associated with increased incidence of CVAE in Ph+ leukemia patients (Figure). In endothelial cells in vitro , we found that dasatinib and ponatinib treatment lead to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib leads to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment lead to phospho-inhibition of endothelial nitric oxide synthase (eNOS) and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and eNOS-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAE in patients receiving BCR-ABL1 TKIs. ROCK inhibition may be a promising approach in reducing the incidence of CVAE associated with second and third generation BCR-ABL1 TKIs.
Abstract 12827: The Prognostic Value of Peak Mitral Annulus Systolic Velocity in Relation to Incident Heart Failure in the General Population - The Copenhagen City Heart Study
Authors: Filip S Davidovski, Mats H Lassen, Kristoffer G Skaarup, Niklas D Johansen, Gorm Boje Jensen, Peter Schnohr, Rasmus Mogelvang, Tor Biering-Srensen
Journal: Circulation (2022)

Introduction: Peak mitral annulus systolic velocity (s’) measured by color tissue Doppler echocardiography can be used to evaluate longitudinal systolic function of the left ventricle (LV). The prognostic value of s’ has previously been documented in patients with ischemic heart disease and heart failure (HF). We sought to investigate the prognostic value of s’ in association with incident HF in the general population with low cardiovascular risk. Methods: This prospective cohort consists of participants from the 5th Copenhagen City Heart Study. All participants had echocardiography performed. Exclusion criteria were prevalent HF, prevalent atrial fibrillation and inadequate image quality for s’ assessment. Multivariable Cox regression models adjusted for; sex, age, smoking-status, diabetes, ischemic heart disease, hypertension, heart rate, left atrial volume index and E/e’, were used to assess the association between s’ and HF. Results: Of 4,110 participants included (mean age 56 years ± 17.4 year, 56.8% female), 90 (2.2%) developed HF during a median follow-up of 5.4 years, [IQR: 4.4-6.3]. The mean s’ was 6.05 cm/s ± 1.2. Following multivariable adjustment, decreasing s’ remained significantly associated with HF (HR 1.60 (95% CI: 1.24; 2.07 p&lt;0.001) per 1 cm/s decrease) (Figure). An optimal cut-off value for s’ was calculated to be 5.9 cm/s. Participants with s’ below this cut-off had a 3-fold increased risk of HF (HR 3.15 (95% CI: 1.97; 5.03 p&lt;0.001). In participants with s’ ≥ 5.9 cm/s, the incidence rate of HF was 2.1 per 1000 person-years (95% CI: 1.39; 3.09) and 6.5 per 1000 person-years (95% CI: 5.13; 8.31) when s’ &lt; 5.9 cm/s. The cut-off value had a sensitivity of 73.3% (95% CI: 63; 82.1), a specificity of 54.0 (95% CI: 52.4; 55.6), and a negative predictive value of 98.9% (95% CI: 98.4; 99.3). Conclusion: In the general population, s’ is an independent prognosticator for the development of HF. Figure. The assocation between s’ and HF.
Abstract 14221: External Validation of Transthyretin Cardiac Amyloid Score Supports Use as Low-Cost Screening Tool
Authors: Joanna S Cavalier, Benjamin Goldstein, Michel G Khouri
Journal: Circulation (2022)

Introduction: Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure. Novel therapies for transthyretin (TTR) CA elevate the need for early identification when treatment has the greatest efficacy. The TTR CA score (TCAS) was recently developed to predict the likelihood of TTR CA in patients undergoing 99mTc-pyrophosphate scintigraphy (PYP) scanning. Its simple inputs could be easily extracted from the electronic health record (EHR), suggesting possible use as a quick, EHR-based screening tool. We perform the first external validation of the TCAS using only EHR-extracted data. We hypothesized that a screening algorithm like TCAS could be generalizable and feasible to implement using our EHR. Methods: EHR data were extracted on all patients at a large academic medical center who underwent PYP scans between 2017 and 2022. PYP scan was considered positive if the patient was part of our institution’s registry of patients with confirmed CA. Inputs - age, sex, echocardiogram wall thickness and ejection fraction, and hypertension diagnosis codes - were converted to TCAS scores. Area under the receiver operating characteristic curve (AUROC) was calculated to analyze predictive performance. Using a TCAS ≥6 as the threshold for high-risk, performance characteristics were calculated. Results: Of 365 patients who underwent PYP scan, 335 had sufficient records to calculate a TCAS. Of these 335 patients, 69 (20.6%) had positive PYP scans. Median TCAS was 5 (interquartile range 4,7). The AUROC was 0.826, with a sensitivity of 87.0%, specificity of 63.9%, positive predictive value of 38.5%, and negative predictive value (NPV) of 95.0%. Conclusions: External validation of the TCAS supports its strong predictive performance with comparable AUROCs to the initial study (0.84-0.89). Clinically, with its high NPV, the TCAS has potential to serve as a simple, low-cost screen to avoid costly PYP scans. We demonstrate the ability to extract all inputs from the EHR, without need for manual chart review or calculation, suggesting that the TCAS could function as an EHR-based screening tool. Low-cost screening tools are needed to identify patients who would benefit from TTR CA workup with PYP scanning, facilitating treatment at earlier disease stages.
Abstract 13187: Inhibition of Advanced Glycation End Products Formation and Serum Protein Infiltration in Bioprosthetic Heart Valves: Investigations of Anti-Glycation Agents
Authors: Andrey Zakharchenko, Christopher A Rock, Tina Thomas, Samuel Keeney, Emily J Hall, Hajime Takano, Giovanni Ferrari, Robert LEVY
Journal: Circulation (2022)

Introduction: Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated bovine pericardium (BP), are the most commonly used heart valve replacements. However, BHV durability is limited by structural valve degeneration (SVD) resulting from both calcification and advanced glycation end product (AGE) deposition together with serum protein infiltration. This study investigated, for the first time, the application of anti-glycation agents as a way to mitigate AGE-related structural degeneration of BHV. Hypothesis: We investigated the hypothesis that anti-AGE agents (Aminoguanidine (AG), Pyridoxamine (PYR), and N-Acetylcysteine (NAC)) could mitigate BP glycation in model studies, both in vitro and in vivo. Methods: To model AGE accumulation in BHV, we used well-established accelerated in vitro glycation models using BP incubation with or without inhibitors. Incorporation of AGE in BP was monitored using radiolabeled glycation precursors. Changes in collagen structure were examined by two photon confocal microscopy and differential scanning calorimetry. In vivo studies used a juvenile rat subdermal BP implantation model with drug administration via drinking water. Endpoints were AGE formation, collagen structure, thermal denaturation temperature, serum albumin uptake, calcification, and serum glycation marker levels. Results: In vitro studies demonstrated that each of these agents significantly inhibited AGE formation in BP. However, after 28-day rat subdermal BP implantation in vivo, only PYR demonstrated significant inhibition of both AGE and serum albumin accumulation per immunostaining. BHV calcification was not mitigated by PYR, AG or NAC. Conclusions: This study is the first to demonstrate the use of AGE inhibitors in mitigating BHV glycation. PYR demonstrated significant efficacy both in vitro and in vivo, mitigating AGE formation and albumin infiltration in BP. Thus, this study provides a rationale for investigating PYR as a possible candidate for improving the durability and biocompatibility of clinically used BHV, providing the solution for this unmet clinical need.
Abstract 12802: Variation by Age in the Use of Telehealth and Remote Monitoring for Patients With Heart Failure in Urban vs. Rural Areas
Authors: Christopher Leggett, James O'Malley, Heather Carlos, Sandra Wong, sally kraft, Matthew Mackwood, Lauren Gilstrap
Journal: Circulation (2022)

Introduction: Limited access is a key challenge in the management of chronic diseases, like heart failure (HF), in rural areas. Telehealth (TH), which is the delivery of care via remote technologies, and remote monitoring (RM), which allows a patient’s implanted device to be interrogated at a distance, are potential ways to improve access. However, many older adults live in rural areas and age is negatively associated with the adoption of novel technologies. The aim of this study is to understand the association between age and use of TH and RM in urban vs. rural areas. Methods: We created annual, cross-sectional cohorts of patients with HF in each year from 2013 to 2018 with approximately 5 million patients/year by requiring ≥1 inpatient or ≥2 outpatient ICD9/10 codes for HF in the 2 years prior. TH and RM use were determined using validated ICD-9/10 and CPT codes. Rurality was determined using the Rural/Urban Commuting Areas (RUCA) classification. Multivariable, logistic regression models were used to determine the association between age and use of TH and RM in urban vs. rural areas. Results: Increasing age was associated with a decreased odds of TH use in both urban and rural areas. However, the decline in use with age was greater in urban (OR=0.41 for 85+ vs 65-69) than rural areas (OR=0.65). In contrast, increasing age was associated with an increased odds of RM in both urban and rural areas, with a larger increase with increase age in rural (OR=1.47 for 85+ vs 65-69) compared to urban areas (OR=1.35). Conclusion: TH and RM are viable ways to improve access for rural patients with HFrEF across the age spectrum. With increasing age, TH use decreases but RM increases, suggesting that patients’ ability to navigate technology plays a significant role - TH technology requires more active engagement by the patient compared to RM technology. Efforts to simplify TH technology would likely mitigate the drop in TH use seen with increasing age and improve access to care for older adults with HFrEF.
Abstract 13695: Is There Utility of Fetal Echocardiogram for Isolated in vitro Fertilization Pregnancies?
Authors: Catherine C Allen, Xiao Zhang, Allie Kiley, Shardha Srinivasan
Journal: Circulation (2022)

Introduction: Risk of congenital heart disease (CHD) for in vitro fertilization (IVF) pregnancies is higher than the general population, though other factors may be involved. IVF is an indication for fetal echocardiogram (FE), however there is center variation to perform FE without a secondary indication if the anatomy ultrasound (AU) is normal. We aim to assess the number of new CHD diagnoses following normal AU in IVF-only pregnancies. Hypothesis: We hypothesize that there is minimal benefit to a FE in IVF-only pregnancies with a normal AU and may result in overutilization of resources. Methods: Retrospective chart review from 2016-2021 of all IVF pregnancies with and without a secondary indication for FE at our center. Those without FE during the COVID-19 pandemic were included to assess postnatal CHD detection. Patients were classified as IVF-only if they had a normal AU and no secondary indication for FE; all others classified as IVF+other. Maternal and fetal demographics, AU, FE, and postnatal echo (post-echo) data was obtained. Results: A total of 556 maternal and 628 fetal patients from IVF pregnancies were included; 401 fetuses were IVF-only with a FE, 116 were IVF-only with no FE, the remaining were IVF+other. There was no complex CHD (CCHD) in either IVF-only groups, the FE group detected several minor findings, and the no FE group detected three small septal defects on post-echo (Table 1). The probability of a normal postnatal evaluation in IVF-only with a normal FE was 94% and with no FE was 96%. Minor variations found on FE triggered additional testing (71 total FE in 43 fetuses) and detected a few minor CHD, none requiring intervention. Conclusions: Given low-risk for CCHD in IVF-only pregnancies, there is minimal benefit to a FE in the setting of a normal comprehensive AU and raises questions of cost vs. benefit of FE. This may impact future recommendations for indications for FE in the setting of IVF-only without added risk factors for CHD.
Abstract 12957: Identifying Reasons for Statin Nonuse in Individuals With Diabetes Using Deep Learning of Unstructured Electronic Health Records
Authors: Ashish Sarraju, Alban Zammit, Summer Ngo, Celeste Witting, Tina Hernandez-Boussard, Fatima Rodriguez
Journal: Circulation (2022)

Introduction: Statins are guideline-recommended and potentially life-saving for individuals with diabetes. Yet, statin use is concerningly low in this group. Identifying reasons for statin nonuse can inform targeted interventions. We hypothesize that clinical reasoning around reasons for statin nonuse may be buried in unstructured, narrative portions of the electronic health record (EHR). We aimed to identify reasons for statin nonuse in patients with diabetes from unstructured EHRs using deep learning. Methods: Adults diagnosed with diabetes from 2014 to 2020 with no statin prescriptions were identified from a multisite EHR health system in Northern California. We used a benchmark deep learning natural language processing (NLP) approach, Clinical Bidirectional Encoder Representations from Transformers (BERT), to identify statin nonuse and reasons for statin nonuse from unstructured EHRs. Clinical BERT was evaluated against expert clinician review in 20% test sets. Results: Of 33,461 patients with diabetes (mean age 59+15y, 49% women, 36% White, 24% Asian, 15% Hispanic), nearly half (47%) lacked statin prescriptions. By leveraging unstructured data containing any mention of statin-related terms, Clinical BERT accurately identified statin nonuse (area under the receiver operating characteristic curve (AUC 0.99 [0.98-1.0]) and identified key patient, clinician, and system reasons for statin nonuse, including statin-associated side effects, guideline-discordant clinician practice, and patient hesitancy (AUC 0.90 [0.86-0.93]; Figure). Conclusions: In a multiethnic diabetes cohort, we identified actionable reasons for statin nonuse using a deep learning approach to mine unstructured EHRs. Findings may enable targeted interventions to improve guideline-directed statin use and be readily scaled to other evidence-based therapies.